Normal human bronchial epithelial (NHBE) cells inoculated at clonal density will multiply with an average generation time of 28 hours; the majority of the cells are small and migratory and have few tonofilaments. Adding human blood-derived serum (BDS) depresses the clonal growth rate of NHBE cells in a dose-dependent fashion. In contrast, 10 representative lines of human lung carcinomas either replicate poorly or fail to grow at all when inoculated at clonal density in serum-free medium; their rates of multiplication increase in direct proportion to the amount of BDS added to the optimized medium. BDS reduces the clonal growth rate of NHBE cells by specifically inducing the normal cells, but not lung carcinoma cells, to undergo squamous differentiation. In vitro carcinogenesis experiments with normal bronchial epithelial tissue and cell cultures have yielded populations of cells with abnormal characteristics. These phenotypically altered cells (PAC), which have keratin epithelial cell markers have extended population doubling potentials, abnormal human karyologies, and reduced response to differentiation control by serum. However, they are not tumorigenic. Human prostatic epithelial cells were transfected by protoplast fusion with the vHa-ras oncogene 34 population doublings post SV-40 virus infection. The transfected cells express the vHa-ras transcripts and phosphorylated P21 protein but, although they express two viral oncogenes, they are not tumorigenic.